The gene causative for the human nonsyndromic recessive form of deafness DFNB22 encodes otoancorin, a 120-kDa inner ear-specific protein that is expressed on the surface of the spiral limbus in the ...cochlea. Gene targeting in ES cells was used to create an EGFP knock-in, otoancorin KO (Otoa ᴱᴳFᴾ/ᴱᴳFᴾ) mouse. In the Otoa ᴱᴳFᴾ/ᴱᴳFᴾ mouse, the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to the spiral limbus and lies over the organ of Corti, retains its general form, and remains in close proximity to the organ of Corti, but is detached from the limbal surface. Measurements of cochlear microphonic potentials, distortion product otoacoustic emissions, and basilar membrane motion indicate that the TM remains functionally attached to the electromotile, sensorimotor outer hair cells of the organ of Corti, and that the amplification and frequency tuning of the basilar membrane responses to sounds are almost normal. The compound action potential masker tuning curves, a measure of the tuning of the sensory inner hair cells, are also sharply tuned, but the thresholds of the compound action potentials, a measure of inner hair cell sensitivity, are significantly elevated. These results indicate that the hearing loss in patients with Otoa mutations is caused by a defect in inner hair cell stimulation, and reveal the limbal attachment of the TM plays a critical role in this process.
The sensory hair cells of amniote hearing organs are usually distributed in tonotopic array from low to high frequencies and are very sensitively and sharply tuned to acoustic stimulation. Frequency ...tuning and tonotopicity of non-mammalian auditory hair cells is due largely to intrinsic properties of the hair cells 1, but frequency tuning and tonotopic organisation of the mammalian cochlea has an extrinsic basis in the basilar membrane (BM); a spiralling ribbon of collagen-rich extracellular matrix that decreases in stiffness from the high-frequency base of the cochlea to the low-frequency apex 2,3. Sensitive frequency tuning is due to amplification, which specifically boosts low-level input to the mechanosensitive hair cells at their tonotopic location to overcome viscous damping 1–3. In non-mammalian hearing organs, at least, amplification is attributed to calcium-mediated hair bundle motion 1. In the mammalian cochlea, amplification is the remit of the sensory-motor outer hair cells (OHCs), located within the organ of Corti to exercise maximum mechanical effect on the motion of the BM and transmit cochlear responses to the adjacent sensory inner hair cells (IHCs) and, consequently, to the auditory nerve 1–3 (Figure 1A). OHCs behave like piezoelectric actuators, developing forces along their long axis in response to changes in membrane potential 2. These forces are due to voltage-dependent conformational changes in the motor molecule prestin, which is densely distributed in the OHC lateral membranes 2.
The round window (RW) membrane provides pressure relief when the cochlea is excited by sound. Here, we report measurements of cochlear function from guinea pigs when the cochlea was stimulated at ...acoustic frequencies by movements of a miniature magnet which partially occluded the RW. Maximum cochlear sensitivity, corresponding to subnanometre magnet displacements at neural thresholds, was observed for frequencies around 20 kHz, which is similar to that for acoustic stimulation. Neural response latencies to acoustic and RW stimulation were similar and taken to indicate that both means of stimulation resulted in the generation of conventional travelling waves along the cochlear partition. It was concluded that the relatively high impedance of the ossicles, as seen from the cochlea, enabled the region of the RW not occluded by the magnet, to act as a pressure shunt during RW stimulation. We propose that travelling waves, similar to those owing to acoustic far-field pressure changes, are driven by a jet-like, near-field component of a complex pressure field, which is generated by the magnetically vibrated RW. Outcomes of research described here are theoretical and practical design principles for the development of new types of hearing aids, which use near-field, RW excitation of the cochlea.
Abstract
Introduction/Objective
With rising healthcare costs in the United States, there has been a push for lab stewardship to improve the quality of patient care while reducing costs. To optimize ...the use of clinical laboratory testing, the ASCP working with other medical specialty organizations, developed the Choosing Wisely Campaign to promulgate evidence-based guidelines to optimize clinical laboratory testing.
Methods/Case Report
We examined adherence to three Choosing Wisely guidelines over a four-year period (2017- 2020), through queries of internal cost accounting databases to return aggregate volumes as well as variable and total costs at three large academic health systems. We measured concurrent orders for: 1) erythrocyte sedimentation rate (ESR) with C-reactive protein (CRP), 2) serum/plasma amylase with lipase, and 3) free thyroxine (FT4) and/or total triiodothyronine (TT3) with thyroid stimulating hormone (TSH) when the TSH is within the reference range (using an frequency estimate of 85% based on other studies). We also examined another guideline for concurrent orders for serum aldolase with creatine kinase (CK). We also quantified aggregate variable costs for the non-recommended test in each Choosing Wisely guideline (amylase, ESR, FT4 and/or TT3), and for serum aldolase when ordered with CK.
Results (if a Case Study enter NA)
Over the four-year period, there were 322,853 unnecessary tests based on these four guidelines (120,587 ESR and CRP, 30,444 amylase and lipase, 164,818 FT4 and/or TT3 with TSH, and 7,004 aldolase). Overall, unnecessary testing decreased between 2017 and 2020 for amylase with lipase, remained essentially unchanged for aldolase, and increased for the other two test guideline scenarios. The largest changes were concurrent orders for amylase and lipase at one health system (38% decrease), and orders for TT3 with a normal TSH result at another health system (324% increase). The four-year variable cost of these unnecessary tests was $1,215,309 ($303,827 mean annual cost), resulting in potential annual variable cost savings of $101,276 for each health system for the four guidelines we examined. Variable costs for unnecessary testing increased by 16.5% ($45,571) over the four-year period.
Conclusion
Guideline-based unnecessary testing remains as a target to improve laboratory diagnostic testing. There is potential to realize significant achievable cost savings if guidelines are implemented and maintained.
Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington’s disease (HD) pathology. A ...high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand 11C-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. 11C-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
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